A major goal of HIV-1 vaccine development is to discover immunogens able to elicit broadly neutralizing antibodies (bNAbs). After more than 25 years of effort, none of the vaccines developed to date have been able to elicit antibodies of this type. For the last decade, the inability to elicit bNAbs has been assumed to result from our lack of success in accurately replicating the trimeric envelope proteins (gp120 and gp41) that compose viral spikes on the virus surface.
Over the last few years, data has emerged suggesting that broadly neutralizing antibodies recognize glycan-dependent epitopes in the HIV-1 envelope protein, gp120 rather than epitopes consisting only of amino acids. More recently, several 3-D structures of broadly neutralizing antibodies binding to HIV-1 envelope proteins have been solved. These have shown that as much as 77% of the binding surface recognized by selected broadly neutralizing monoclonal antibodies (bN-MAbs) is composed of carbohydrate.
Moreover these studies show that the epitope recognized by the prototypic PG9 MAb (16) was located in the V1/V2 domain of gp120 and dependent on mannose-5 for binding. Similarly, another epitope recognized by the prototypic MAb PGT128 (15) is located at the stem of V3 loop and depended on mannose-9 for binding.
Since these bN-MAbs exhibit little if any binding to monomeric gp120, but exhibit robust binding to trimeric envelopes on the surface of cells or viruses, these antibodies were thought to recognize epitopes dependent on both carbohydrate and on the quaternary structure of the envelope trimers (8, 15). Studies of the ontogeny of PG9-like antibodies (3) demonstrated the germline precursor of PG9 and PG9-like antibodies are unable to bind to most monomeric gp120 proteins.
However, one notable exception was gp120 from the A244 strain of HIV-1. Our lab originally determined the sequence of this virus in the early 1990s (7) and has worked with this protein for many years. Indeed this protein was a major component of the AIDSVAX B/E vaccine developed at Genentech and then licensed to VaxGen (1, 2). This vaccine failed to provide protection (11) in a Phase 3 trial (VAX003) carried out in Thailand (1998-2003). However modest but significant protection (31.4% efficacy) was achieved when this vaccine was combined with another vaccine vCP1521 in the RV144 trial involving more than 16,000 volunteers that ended in 2009 (12).